PROJECT SUMMARY/ABSTRACT In the United States (U.S.), endometrial cancer (EC) incidence is increasing among women of all racial subgroups; however, black women are experiencing the most dramatic increases. It is well known that obesity increases EC risk more so than any other cancer. As the prevalence of obesity continues to rise, the burden of EC will also grow, underscoring the need for effective primary prevention strategies. Evidence on the reversibility of EC risk through weight loss is emerging. To effectively intervene to reduce EC risk, we must identify the biological mechanisms that underlie associations between weight loss and lower EC risk. The primary goals of this proposal are to examine how changes in body composition following weight loss impact inflammatory biomarkers in biopsy-collected endometrial tissue and serum and whether these processes differ between black and white women. Inflammation is linked with excess adiposity and associated with higher risk of developing EC. The applicant will conduct a pilot cohort study enrolling 40 black and 40 white women medically cleared and scheduled to undergo bariatric surgery and 20 black and 20 white women enrolled in a non-surgical weight loss program (controls). At baseline, we will assess EC risk factors with a questionnaire, measure body composition using dual x-ray absorptiometry (DXA), conduct endometrial tissue biopsies and blood draws for biomarker characterizations, and assess endometrial hyperplasia (EH), an EC precursor lesion, using a pathology review (Aim 1). Six months after the surgical or non-surgical weight loss intervention, we will measure body composition and inflammation in tissue and serum to assess changes following weight loss (Aim 2), and we will explore racial differences in baseline and time-dependent relationships (Aim 3). Findings from this K01 application will increase our understanding of the effect of excess adiposity on inflammation and cancer initiation within the local endometrial environment and provide higher resolution data on adiposity through use of DXA as compared with previous studies that only use body mass index. Further, this study will add novel data on racial differences in these processes and generate new hypotheses regarding EC prevention. In addition to a novel line of research, the applicant proposes a well-defined program of training crucial for the applicant to obtain subject-matter expertise and proficiencies applicable to the proposed research. The applicant will receive training in: the design and conduct of prospective epidemiological and clinical studies; health disparities research; body composition; the biology of adiposity and cancer; development of intervention studies; longitudinal data analysis; translational research; and bioinformatics analysis. This training will be achieved through coursework, attendance at workshops, seminars, conferences, and most importantly, hands-on mentored research from a highly qualified team of mentors and collaborators, reflecting multiple disciplines. The intensive training plan and innovative research outlined in this K01 application will prepare the applicant to successfully transition into an independent investigator focused on the molecular mechanisms that underlie the obesity-EC risk relationship.